Systemic Disease and the Eye

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Morning Report 2/16/2010 Cooper University
Hospital
BEHÇETS DISEASE
Jean Pierre El Khoury, MD
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Case Presentation

• 39 years old Israeli female p/w Chronic diarrhea
  and rash to her legs
• PMH
• SLE
• ITP
• Alopecia
• HTN
• Meds
• Plaquenil, Prednisone, Tylenol, Demerol, Gravol

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HPI

• Patient had 2 month history of watery stools
• 18 lbs weight loss , secondary to ?appetite
• Denies Nausea, Vomiting, Abdominal pain.
• No travel history. No Headache. No fevers. No
  cough
• Recent UTI treated with Bactrim
• The lower extremities rash started 1 month ago
  and was followed by oral ulcers and
  conjunctivitis / blepharitis

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Physical exam

• VS Temp 38.5 BP 128/90 HR 105 RR 16
  SaO2 99 on R/A
• HEENT
• No lymphadenopathy, No thyromegaly, Blepharitis,
  Conjuctival injection, Oral ulcers to tongue and
  lips.
• CV
• Normal S1/S2, No murmurs, rubs or gallops
• Lungs
• CTA B/L , No crackles/Ronchi/wheezing
• GI
• Normal BS, Soft Abdomen, Non-tender,
  Non-distended, No Peritoneal signs, no HSM/
  Ascites, No masses
• Musculoskeletal
• No active joints effusion, Normal muscle bulk/
  tone/ power
• Skin
• Erythematous, swollen nodules bilaterally to L/E

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Initial Studies

• WBC 11.66 (neut 90)
• Hb 13
• Plt 262
• Chem 7 Normal
• LFTs AST 78, Alb 2.8
• Stool negative for OP, C.Diff toxin negative x1
• Anti ds DNA and ANA negative, C3/C4 Normal
• CXR Normal
• Abdominal X-rays Air fluid levels
• Abdominal U/S Unremarkable
• Urine and blood Cultures No growth

• ESR 92
• CRP 96.2
• TSH 0.34, free T4 Nl
• CMV negative

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More Investigations !!

• Colonoscopy with Sigmoid biopsy
• Acute chronic inflammatory inflitrates
• No granulomas, no dysplasia, no malignancy
• no convincing evidence of vasculitis
• Possible etiologies resolving infection or
  drugs.
• Skin biopsy
• Adipose tissue panniculitis with septal acute
  and chronic inflammation
• No evidence of arteritis
• Appearance consistent with erythema nodosum

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Diagnosis made !
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Hospital Course

• Patient was started on Solumedrol 20mg IV bid and
  switched to po after 5days. Both diarrhea and EN
  rash resolved
• D/C home on prednisone taper (60mg?50mg),
  Plaquenil, Alendronate, Vit D Ca
• F/U arranged with Rheumatology, GI

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BEHÇETS DISEASE

• Idiopathic multisystem disease
• More common in men
• Occurs in 3rd - 4th decade
• Highest incidence in Mediterranean region and
  Japan
• Associated with HLA-B5

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BEHÇETS DISEASEEtiology

• Unknown
• Various bacteria and viruses suggested
• No good evidence to suggest any of them
• Perpetuated by autoimmune response and CD4
  T-cells
• Tumour necrosis factor (TNF) thought to be
  important

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BEHÇETS DISEASEPathophysiology

• BD has been classified among the systemic
  vasculitis
• Its a vasculitis or vasculopathy with
  perivascular inflammatory cell infiltrates and
  thrombotic tendency has been documented as the
  main pathological finding in BD lesions

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BEHÇETS DISEASE Systemic Involvement (1)

• Oral aphthous ulceration 100
• Lesions heal within about 10 days without
  scarring

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BEHÇETS DISEASE Systemic Involvement (2)

• Genital ulceration 90

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BEHÇETS DISEASE Systemic Involvement (3)

• Skin lesions 80
• Erythema Nodosum
• Pyoderma Gangrenosum
• Palpable Prupura
• Acneiform lesions
• Uveitis 70 (inflam. of iris, ciliary body or
  choroid)

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Clinical Manifestations Cutaneous Lesions

• Pathergy refers to an erythematous papular or
  pustular response to local skin injury.
• Defined as a greater than 5 mm lesion that
  appears 24 to 48 hours after skin prick by a
  needle.
• The pathergy test can also be positive in Sweet's
  syndrome and pyoderma gangrenosum.

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BEHÇETS DISEASE Systemic Involvement (4)

• CNS involvement strokes
• Major vessels
• Eg Sup Vena Cava obstruction
• Non-erosive, asymetric, non-deforming Arthritis

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Vascular disease in 728 patients with Behcet's
disease
Number of patients
Venous disease Venous disease
Deep venous thrombosis 221
Subcutaneous thrombophlebitis 205
SVC occlusion 122
IVC occlusion 93
Cerebral sinus thrombosis 30
Budd-Chiari syndrome 17
Other venous occlusion 24
Arterial disease Arterial disease
Pulmonary artery occlusion or aneurysm 36
Aortic aneurysm 17
Extremity arterial occlusion or aneurysm 45
Other arterial occlusion or aneurysm   42
Right ventricular thrombus 2
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BEHÇETS DISEASEOcular Features (1)

• Acute iritis
• Pain, redness ?VA
• Inflammatory cells in anterior chamber
• Recurrent hypopyon
• (Fluid level of WBC)
• The red or white eye
• Bilateral and Episodic !

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BEHÇETS DISEASEOcular Features (2)

• Marked inflammation of the eye
• Retinal vasculitis and haemorrhage (inflam. of
  retinal vessels)
• Occlusive periphlebitis (venous sheathing
  occlusion)
• Retinal microinfarcts
• Very damaging to vision retinal damage and optic
  nerve atrophy
• Cataract or glaucoma

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Eye involvement, arterial aneurysms, DVT,
parenchymal neurological disease require prompt
and effective treatement to prevent irreversible
tissue damage.
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Behcets Disease Diagnosis

• There are no pathognomonic symptoms or laboratory
  findings, the diagnosis is made on the basis of
  clinical findings
• International criteria were published in 1990

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BEHÇETS DISEASETreatment

• Systemic Steroids
• Systemic immunosuppressive agents
• Interferon-alpha may have immunodulating effects
• Anti-TNF monoclonal antibodies may be of help

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Behcets Disease Prognosis

• Behcet's disease has an undulating course of
  exacerbations and remissions, and may become less
  severe after approximately 20 years.
• The disease appears to be more severe in young,
  male, and Middle Eastern or Far Eastern patients.

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Behcets Disease Prognosis

• Mucocutaneous, articular and ocular disease are
  often at their worst in the early years of
  disease.
• Central nervous system and large vessel disease,
  if they develop, typically do so later in the
  disease course.

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Behcets Disease Prognosis

• In one study, 20 percent of patients with chronic
  neurologic involvement died within seven years.
• Half of patients die within three years after the
  onset of hemoptysis.
• There NO laboratory findings that have helped to
  predict the BD patient with a worse prognosis.

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Goals of Management
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Goals of Management

• Evaluation of prognostic factors and
  identification of high-risk patients at early
  stages of the disease is critical for tailoring
  treatment according to severity of the disease
  and planning optimal treatment
• Limited number of RCTs (Multisystem Disease,
  Gender varitation, previous treatement
  characteristics, variability in recurrences
  rates)

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Treatment of Inflammatory AttacksTreat without
delay !!
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Mucocutaneous lesions

• Topical Corticosteroids O G No RCTs !!
• Topical Sucralfate suspension x 4/day
• gt Reduce healing time pain of O G
• Rebamipide 300mg/day gt reduce Pain of Oral
  ulcers but as an adjunctive treatment.
• INFa2a gt improved duration Pain of O

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Acute Arthritis

• Azapropazone (NSAID) for 3 weeks gt
• NO EFFICACY !!!
• - No other NSAIDs or Corticosteroids have been
  formally assessed for Acute Arthritis in BD

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Intraocular inflammation

• Corticosteroids for acute uveitis No RCTs!!
• Topical Corticosteroids for anterior Uveitis
• Periorbital injections for intermediate uveitis
  or macular oedema
• Intravitreal triamcinolone (Nasacort) for cystoid
  macular oedema secondary to BD
• Systemic Corticosteroids for posterior uveal
  segment involvement or retinal vasculitis

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Intraocular inflammation
2-4 weeks
Infliximab
10mg/kg ?
INFa2a
Ciclosporine
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• gt 50 improvement in the degree of
  inflammation within the first 24 hours, and
  complete suppression within 7 days after the
  infusion of Infliximab 5 mg/kg in five BD
  patients with sight-threatening uveitis.

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Major vessel disease, neurological, intestinal
involvement ?

• NO RCTs !!
• Corticosteroids Immunosuppressive drugs
• Pulmonary artery aneurysm Corticosteroids
  Cyclophosphamide
• The place of anticoagulants as well as the
  combination of corticosteroids and
  immunosuppressive drugs for the treatment of
  acute thrombotic events has long been debated by
  the experts. Moreover their use may increase the
  risk of fatal bleeding in patients with arterial
  aneurysms.

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Prevention of Relapses
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Prevention of Relapses

• Colchicine 1-2mg/day
• Reduce the frequency of genital ulcers, erythema
  nodosum, arthritis among women
• Reduce the frequency of --------------------------
  ------------------- arthritis among men
• Thalidomide 100mg/day
• Reduce the recurrence of oral genital ulcers
• Increase the risk of polyneuropathy
• Increase the frequency of erythema nodosum-like
  lesions superficial thrombophlebitis
• ? reserved mucocutaneous lesions resistant to
  other treatments.
• Rebamipide 300mg/day gt Reduce Oral Ulcers
• Dapsone 100mg/day gt frequency of mucocutaneous
• Lower doses of corticosteroids
• Methylprednisolone acetate 40mg IM every 3 weeks
  for 27 weeks gt The only benefit is a reduction
  in the recurrence of erythema nodosum lesion,
  mainly in women.

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Prevention of Relapses

• - Ciclosporin (Unacceptably High dose)
• Effective for Uveitis, O G, skin lesions during
  16 weeks period
• - Azathioprine 2.5mg/kg
• Effective in controling eye disease, less
  frequent O G, less arthritis
• (Long-term analysis, more effective with a
  shorter disease duration lt2years)
• - Chlorambucil Tacrolimus NO evidence!
• In a series of 808 BD patients with uveitis who
  were treated with conventional immunosuppressive
  agents, the risk of losing vision at 7-year
  follow-up was 21, But No RCTs !!
• - Recombinant human INFa2a starting at 6MIU/day
  and decreasing doses gt Response rate of 92 in
  50 BD with sight-threatening uveitis or retinal
  vasculitis Remission achieved at week 24.

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Prevention of Relapses

• - Infliximab 5 or 10mg/kg (week 0, 2, 6 10)
• Ohno colleagues evaluated Infliximab in 13 BD
  with uveoretinitis resistant to ciclosporin gt
  Mean number of ocular attacks decreased from 3.96
  to 0.98 for 5mg/kg and from 3.79 to 0.16 for
  10mg/kg (Over 14 weeks).
• Another group of 13 BD who had gt 2 attacks of
  posterior/panuveitis or retinal vasculitis
  despite Azathioprine, Ciclosporin
  Corticosteroids after 6 months, received
  Infliximab 5 mg/kg (week 0, 2, 6, 14)
• Week (-6) - 0 6-month previous-treatment
  Period
• Week 0-22 Infusion Period
• Week 23-54 Observation Period

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• Infliximab
• gt Attack-free remission in 31 during the
  Infusion Period
• gt In the remaining 69 less frequent less
  severe Uveitis Attacks compared to the 6month
  previous-treatment Period and Observational
  Period.
• gt A sustained remission for up to 54 weeks in
  1/13 which indicated that the Treatment should
  be continued to maintain the beneficial effects
  in most patients.
• gt 77 of the uveitis attacks that were observed
  during the infusion period occurred at the end of
  the 8-week period that followed the last
  Infliximab infusion (i.e. at either 14 or 22
  weeks) ? The authors suggested that the remission
  rate may have been higher with shorter infusion
  intervals.

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Prevention of Relapses

• Antigen-specific immune responses have been
  demonstrated against 4 peptides from microbial
  heat shock protein (HSP)-65 and the homologous
  human-HSP60 in BD.
• A recent phase I/II trial was performed to assess
  the efficacy of oral tolerisation with
  BD-specific HSP60 peptide linked to a recombinant
  cholera toxin B subunit (3/sem)
• gt NO Adverse effect
• gt 5/8 BD with ocular involvement were able to
  withdraw their immunosuppressive drugs
  gradually over a period of 6-9 weeks
  without relapse of uveitis.
• gt 3/5 responding patients remained free of
  relapsing uveitis for 10-18 months after
  tolerisation was discontinued.
• A randomized, prospective trial was conducted to
  evaluate the effectiveness of benzathine
  benzylpenicillin combined with colchicine in the
  prophylaxis of recurrent arthritis in BD.
• gt Significantly lower numbers of arthritis
  episodes and longer episode-free periods were
  observed in patients receiving both v/s only
  Colchicine for 24 months

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Take Messages !!

• Early and effective treatment of acute
  inflammatory lesions and prevention of relapses
  can help to reduce the disease burden and improve
  outcome.
• RCTs are limited but have documented favourable
  effects of a lot of immunosuppressive drugs for
  various BD manifestations.
• More potent drugs are effective in the
  suppression of more severe systemic features as
  well as mucocutaneous manifestations.
• Although no RCTs are yet available , results of
  open studies with both INFa2a and Infliximab are
  promising for those patients with disease
  resistant to conventional immunosuppressive
  treatments.
• More trials are required to provide more
  generalisable results, which can lead to better
  management plans.

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